Treatment outcome comparisons of first-line targeted therapy in patients with KRAS wild-type metastatic colorectal cancer: A nationwide database study.

BACKGROUND: The first-line systemic therapy for metastatic colorectal cancer (mCRC) is a combination of one targeted therapy agent and a chemotherapy doublet. Whether bevacizumab or anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) is the more effective addition to a chemotherapy doublet as the first-line treatment for inoperable KRAS wild-type mCRC remains controversial in prior clinical trials. Moreover, the association between the sidedness of primary tumors and the efficacy of anti-EGFR mAb needs to be addressed. METHODS: We established a cohort of patients with KRAS wild-type mCRC who were treated with first-line targeted therapy plus doublet chemotherapy between 2013 and 2018 using Taiwan's National Health Insurance Research Database. Secondary surgery was defined as either resection of primary tumors, liver metastases, lung metastases, or radiofrequency ablation. RESULTS: A total of 6482 patients were included; bevacizumab and anti-EGFR mAb were the first-line targeted therapies in 3334 (51.4%) and 3148 (48.6%) patients, respectively. Compared with those who received bevacizumab, patients who received anti-EGFR mAb exhibited significantly longer overall survival (OS; median, 23.1 vs. 20.2 months, p = 0.012) and time to treatment failure (TTF; median, 11.3 vs. 10 months, p < 0.001). Among left-sided primary tumors, the OS and TTF benefits of anti-EGFR mAb remained. Among right-sided primary tumors, the OS and TTF were similar regardless of the type of targeted therapy. In multivariate analyses, first-line anti-EGFR mAb therapy remained an independent predictor of longer OS and TTF for left-sided primary tumors. Patients who received anti-EGFR mAb were more likely to receive secondary surgery (29.6% vs. 22.6%, p < 0.0001) than patients who received bevacizumab. CONCLUSION: For patients who received first-line doublet chemotherapy for KRAS wild-type mCRC, adding anti-EGFR mAb was associated with significantly longer OS and TTF, especially for left-sided primary tumors.

Different immune contextures underlie tumor site-specific responses to immune checkpoint blockade in esophageal cancer.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in advanced esophageal squamous cell carcinoma (ESCC). Heterogeneous responses to ICIs have been reported previously. Here, we describe a patient with advanced ESCC exhibiting a response to durvalumab plus tremelimumab for more than 6 months except primary resistant esophageal tumor. The esophageal tumor had higher regulatory T cells, neutrophils, and mast cells scores estimated by NanoString platform than hepatic tumor. The immunohistochemistry study confirmed higher expression levels of Foxp3, and myeloperoxidase (MPO) in the esophageal tumor. The different immune contextures may underlie the heterogeneous responses to ICI combination in this ESCC patient.

Cancer-Associated Thrombosis: A Taiwanese Perspective on Therapeutic Options with Focus on Non-Vitamin K Antagonist Oral Anticoagulants.

Cancer-associated thrombosis (CAT) is a common complication of malignancies. Patients with CAT are at risk of venous thromboembolism recurrence, but also at risk of bleeding while anticoagulated. Taiwanese patients are perceived to have a lower incidence of CAT, likely leading to false reassurance for Taiwanese patients with cancer. Because of this, oncologists and cardiologists from multiple medical institutions in Taiwan have set forth to provide clinical consensus guidelines on the management of CAT, based on local clinical practices and guided by predominant international clinical practice guidelines. This paper aims to describe the current disease burden of cancer-associated venous thromboembolism in Taiwanese cancer patients, and discusses the unmet needs and gaps in the management of this medical complication. It also outlines diagnostic and management strategies relevant to the different treatment options available, such as non-vitamin K antagonist oral anticoagulants.

Sarcopenia and myosteatosis are associated with survival in patients receiving immunotherapy for advanced hepatocellular carcinoma.

OBJECTIVES: To investigate the association of sarcopenia, myosteatosis, and sarcopenic obesity with survival outcomes among patients who underwent immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective analysis, patients who initiated immunotherapy for advanced HCC were enrolled. Sarcopenia and myosteatosis were evaluated on pretreatment CT at L3 level by skeletal muscle index and mean muscle attenuation using predefined cutoff values. Sarcopenic obesity was defined as concurrent sarcopenia and body mass index > 25 kg/m2. The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 138 patients was included (discovery cohort n = 111, validation cohort n = 27). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p = 0.048) and OS (p = 0.002) than patients without sarcopenia. Patients with myosteatosis exhibited significantly poorer PFS (p < 0.001) and OS (p < 0.001) than patients without myosteatosis. Patients with sarcopenic obesity compared to patients without sarcopenic obesity exhibited significantly poorer OS (p = 0.006) but not PFS (p = 0.31). In multivariate analysis adjusting for patient demographics, tumor extent, and liver function reserve, myosteatosis remained an independent predictor of poor PFS (p = 0.014) and OS (p = 0.007); sarcopenia remained an independent predictor for poor OS (p = 0.007). The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort. CONCLUSIONS: Sarcopenia and myosteatosis are independent prognostic factors in patients who received immunotherapy for advanced HCC. KEY POINTS: • Sarcopenia and myosteatosis can be evaluated by CT at L3 level. • Sarcopenia, myosteatosis, and sarcopenic obesity were associated with poor survival outcomes in patients who underwent immunotherapy for advanced HCC. • Myosteatosis was an independent predictor of PFS and OS, and sarcopenia was independent for OS in these patients.

Artificial intelligence-based immunoprofiling serves as a potentially predictive biomarker of nivolumab treatment for advanced hepatocellular carcinoma.

Immune checkpoint inhibitors (ICI) have been applied in treating advanced hepatocellular carcinoma (aHCC) patients, but few patients exhibit stable and lasting responses. Moreover, identifying aHCC patients suitable for ICI treatment is still challenged. This study aimed to evaluate whether dissecting peripheral immune cell subsets by Mann-Whitney U test and artificial intelligence (AI) algorithms could serve as predictive biomarkers of nivolumab treatment for aHCC. Disease control group carried significantly increased percentages of PD-L1+ monocytes, PD-L1+ CD8 T cells, PD-L1+ CD8 NKT cells, and decreased percentages of PD-L1+ CD8 NKT cells via Mann-Whitney U test. By recursive feature elimination method, five featured subsets (CD4 NKTreg, PD-1+ CD8 T cells, PD-1+ CD8 NKT cells, PD-L1+ CD8 T cells and PD-L1+ monocytes) were selected for AI training. The featured subsets were highly overlapping with ones identified via Mann-Whitney U test. Trained AI algorithms committed valuable AUC from 0.8417 to 0.875 to significantly separate disease control group from disease progression group, and SHAP value ranking also revealed PD-L1+ monocytes and PD-L1+ CD8 T cells exclusively and significantly contributed to this discrimination. In summary, the current study demonstrated that integrally analyzing immune cell profiling with AI algorithms could serve as predictive biomarkers of ICI treatment.

Bevacizumab and atezolizumab as first-line therapy for advanced hepatocellular carcinoma: A Taiwanese subgroup analysis on efficacy and safety.

BACKGROUND: The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials. METHODS: All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records. RESULTS: We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed. CONCLUSION: In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations.

Cyclin-Dependent Kinase 9 Inhibition as a Potential Treatment for Hepatocellular Carcinoma.

PURPOSE: Composite cyclin-dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC. METHODS: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition. RESULTS: CDK9 inhibitors exhibited potent antiproliferative activities in HCC cells regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1 and survivin. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited significantly slower tumor growth than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving a CDK9 inhibitor also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Knockdown of CDK9 expression reduced the proliferative activities of HCC cells. CONCLUSION: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.

Expanding Sorafenib Treatment for Hepatocellular Carcinoma Beyond Barcelona Clinic Liver Cancer Stage C Patients: A National Study.

BACKGROUND/AIM: The reimbursement criteria of sorafenib for advanced hepatocellular carcinoma (HCC) were expanded in 2016 by Taiwan's National Health Insurance (NHI) to include patients without macrovascular invasion or extrahepatic spread. This study explored sorafenib treatment outcomes before and after this expansion. PATIENTS AND METHODS: The NHI database was searched for patients who initiated sorafenib treatment between January 1, 2013, and December 31, 2017. Clinical variables were retrieved from the Taiwan Cancer Registry database. Overall survival (OS) and time to treatment discontinuation (TTD) were calculated as the times from the first sorafenib prescription date until death and the final prescription date, respectively. RESULTS: A total of 13,862 patients were included. The median age was 64 years, 78.1% of patients were male. Approximately a quarter of patients (25.1%) received sorafenib after the criteria expansion and exhibited significantly longer OS (median 7.9 vs. 6.6 months, p<0.001) and TTD (median 3.0 vs. 2.6 months, p=0.003) compared with patients who started before. These results were verified in patients with available data regarding clinical prognostic factors (n=9,378, 67.7% of the entire study population). In the multivariate analysis, sorafenib prescription after criteria expansion remained an independent predictor of longer OS [hazard ratio (HR)=0.87, p<0.001] and TTD (HR=0.93, p=0.004). In the subgroup analysis, these trends were consistently observed across different patient subgroups. CONCLUSION: Patients with HCC who received sorafenib treatment after the reimbursement criteria expansion exhibited longer OS and TTD.

Prognosis and treatment pattern of advanced hepatocellular carcinoma after failure of first-line atezolizumab and bevacizumab treatment.

BACKGROUND: The combination of atezolizumab and bevacizumab (Atezo-Bev) has become the standard first-line therapy for patients with advanced hepatocellular carcinoma (HCC), but the prognosis and treatment pattern after its treatment failure are unclear. METHODS: We reviewed the medical records of patients who failed first-line Atezo-Bev treatment for advanced HCC from January 2018 to May 2021 in four Taiwan medical centers. Post-first-line survival (PFLS) was defined as the date from the failure of Atezo-Bev treatment to the date of death or last follow-up. RESULTS: A total of 41 patients were included in the study. All patients had Child-Pugh A liver reserve before the initiation of Atezo-Bev treatment, but the liver reserve of 6 (15%) and 7 (17%) patients deteriorated to Child-Pugh B and C, respectively, after treatment failure. The median PFLS was 5.9 months. PFLS significantly differed among patients with various liver reserves after the failure of Atezo-Bev treatment (median 9.6 vs 3.8 vs 1.2 months, for Child-Pugh A, B, and C; p < 0.001). In total, 30 (73%) patients received second-line systemic therapy, and they exhibited significantly longer PFLS (median 8.0 vs 1.8 months, p = 0.033) than patients who did not. Deteriorated liver function and not receiving second-line therapy remained associated with inferior PFLS in multivariate analysis. The most common second-line therapies were sorafenib (n = 19, 63%) and lenvatinib (n = 9, 30%), with no significant differences in efficacies. CONCLUSION: Receiving second-line therapy and good liver reserve were associated with favorable PFLS after the failure of first-line Atezo-Bev treatment.

ICOS-Positive Regulatory T Cells in Hepatocellular Carcinoma: The Perspective from Digital Pathology Analysis.

INTRODUCTION: Inducible co-stimulator (ICOS), an important co-stimulatory receptor on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC). METHODS: Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center. Dual immunohistochemistry was performed to evaluate the expression of ICOS and Foxp3. The cell densities and proximities between stained cells in regions of interest were measured by digital pathology and the associations with clinical outcome were analyzed. RESULTS: A total of 142 patients (male:female = 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus infection and 33 (23.2%) had chronic hepatitis C infection. Low α-fetoprotein level (<20 ng/mL) and early-stage were significantly associated with improved overall survival (OS). The density of ICOS+Foxp3+ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p < 0.001) in the tumor center than in the peritumor area. Patients with a high density of ICOS+Foxp3+ cells or a high ratio of ICOS+Foxp3+/total Foxp3+ cells in the tumor center trended to have a shorter OS. A shorter distance between ICOS+Foxp3+ cells and ICOS+Foxp3- cells (likely Teffs) in the tumor center was significantly associated with a shorter OS (p = 0.030), suggesting active immunosuppression of ICOS+ Tregs on ICOS+ Teffs. CONCLUSION: An increased abundance of ICOS+ Tregs in the tumor center in comparison to the peritumor area indicates a strong immunosuppressive tumor microenvironment of HCC. A high proportion of ICOS+Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells were associated with a poor OS, suggesting that depleting ICOS+ Tregs might provide clinical benefit for patients with HCC.

Low miR-10b-3p associated with sorafenib resistance in hepatocellular carcinoma.

BACKGROUND: Sorafenib is one of the standard first-line therapies for advanced hepatocellular carcinoma (HCC). Unfortunately, there are currently no appropriate biomarkers to predict the clinical efficacy of sorafenib in HCC patients. MicroRNAs (miRNAs) have been studied for their biological functions and clinical applications in human cancers. METHODS: In this study, we found that miR-10b-3p expression was suppressed in sorafenib-resistant HCC cell lines through miRNA microarray analysis. RESULTS: Sorafenib-induced apoptosis in HCC cells was significantly enhanced by miR-10b-3p overexpression and partially abrogated by miR-10b-3p depletion. Among 45 patients who received sorafenib for advanced HCC, those with high miR-10b-3p levels, compared to those with low levels, exhibited significantly longer overall survival (OS) (median, 13.9 vs. 3.5 months, p = 0.021), suggesting that high serum miR-10b-3p level in patients treated with sorafenib for advanced HCC serves as a biomarker for predicting sorafenib efficacy. Furthermore, we confirmed that cyclin E1, a known promoter of sorafenib resistance reported by our previous study, is the downstream target for miR-10b-3p in HCC cells. CONCLUSIONS: This study not only identified the molecular target for miR-10b-3p, but also provided evidence that circulating miR-10b-3p may be used as a biomarker for predicting sorafenib sensitivity in patients with HCC.

Association of annexin A10 expression with poor prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Annexin A10 expression influences the prognosis of several gastrointestinal cancers. We explored the association of annexin A10 expression with the overall survival (OS) of patients who underwent curative surgery for cholangiocarcinoma. METHODS: Patients who underwent curative surgery for cholangiocarcinoma (except gallbladder cancer) and had pathological stage T1-3N0M0 disease were enrolled. Annexin A10 expression was examined by performing immunohistochemical staining. Patient demographics and survival outcome data were retrieved from medical records. RESULTS: In total, 185 patients were enrolled. The primary tumor location was intrahepatic and extrahepatic (including the perihilar region) for 89% and 11% of patients, respectively. Positive annexin A10 staining was detected for 61 (33%) patients and associated with extrahepatic or perihilar cholangiocarcinoma (p = 0.001) and lower histological grade (p < 0.001). Patients with positive annexin A10 staining exhibited significantly poorer survival relative to patients with negative staining results (median OS, 2.5 vs. 4.9 years, p = 0.025). In the multivariate analysis adjusting for age, sex, tumor location, tumor grade, hepatitis infection, and disease stage, positive annexin A10 remained an independent predictor of poor OS (hazard ratio 1.572, p = 0.034). In the subgroup analysis, the association between annexin A10 and prognosis was restricted to intrahepatic cholangiocarcinoma. Among patients with intrahepatic cholangiocarcinoma, patients with positive annexin A10 staining exhibited significantly poorer survival compared with patients with negative annexin A10 staining (median OS, 2.3 vs. 4.9 years, p = 0.008). CONCLUSION: Positive annexin A10 expression was associated with poor prognosis of intrahepatic cholangiocarcinoma.

Anti-PD-1 combined sorafenib versus anti-PD-1 alone in the treatment of advanced hepatocellular cell carcinoma: a propensity score-matching study.

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a role in the tumor microenvironment. Sorafenib, which inhibits the VEGF pathway, has an immune-modulation function but lacks substantial clinical data. This study aims to explore the efficacy of anti-PD-1 combined sorafenib in advanced hepatocellular carcinoma (HCC). METHODS: HCC patients who underwent anti-PD-1 treatment at Taipei Veterans General Hospital (Taipei, Taiwan) between January 2016 and February 2019 were reviewed. The efficacy was compared between groups after propensity-score matching. RESULTS: There were 173 HCC patients receiving anti-PD-1. After excluding unsuitable cases, 140 patients were analyzed, of which 58 received combination therapy and 82 received anti-PD-1 alone. The combination therapy had a trend of higher CR rate (8.6% vs. 4.9%, ns.), ORR (22.4% vs. 19.5%, ns.) and significantly higher DCR (69.0% vs. 37.8%, p < 0.05) comparing to anti-PD-1 alone. After matching, combination group achieved longer progression-free survival (3.87 vs. 2.43 months, p < 0.05) and overall survival (not reached vs. 7.17 months, p < 0.05) than anti-PD-1 alone, without higher grade 3/4 AE (10.3% vs. 7.1%, p = 0.73). The tumor response varied among different metastatic sites, with high responses in adrenal glands, peritoneum and lungs. The more AFP declined (> 10, > 50 and > 66%), the higher the ORR (70, 80 and 92%) and CR rates (30, 35 and 58%) were achieved at day 28. CONCLUSIONS: This is the first study to demonstrate the combination of anti-PD-1 and sorafenib had better efficacy and survival benefit. A prospective randomized study is needed to confirm this finding.

Revisiting Hepatic Artery Infusion Chemotherapy in the Treatment of Advanced Hepatocellular Carcinoma.

Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC.

Early Changes in DCE-MRI Biomarkers May Predict Survival Outcomes in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: Two Prospective Phase II Trials.

In this paper, our main objective was to predict survival outcomes using DCE-MRI biomarkers in patients with advanced hepatocellular carcinoma (HCC) after progression from 1st-line sorafenib treatment in two prospective phase II trials. This study included 74 participants (men/women = 64/10, mean age 60 ± 11.8 years) with advanced HCC who received 2nd-line targeted therapy (n = 41 with lenalidomide in one clinical trial; n = 33 with axitinib in another clinical trial) after sorafenib failure from two prospective phase II studies. Among them, all patients underwent DCE-MRI at baseline, and on days 3 and 14 of treatment. The relative changes (Δ) in the DCE-MRI parameters, including ΔPeak, ΔAUC, and ΔKtrans, were derived from the largest hepatic tumor. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The Cox model was used to investigate the associations of the clinical variables and DCE-MRI biomarkers with progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was 10.8% (8/74) and the disease control rate (DCR) was 58.1% (43/74). The median PFS and OS values were 1.9 and 7.8 months, respectively. On day 3 (D3), participants with high reductions in ΔPeak_D3 (hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.17-0.93, p = 0.017) or ΔAUC_D3 (HR 0.51, 95% CI 0.25-1.04, p = 0.043) were associated with better PFS. On day 14, participants with high reductions in ΔPeak_D14 (HR 0.51, 95% CI 0.26-1.01, p = 0.032), ΔAUC_D14 (HR 0.54, 95% CI 0.33-0.9, p = 0.009), or ΔKtrans_D14 (HR 0.26, 95% CI 0.12-0.56, p < 0.001) had a higher PFS than those with lower reduction values. In addition, high reductions in ΔAUC_D14 (HR 0.53, 95% CI 0.32-0.9, p = 0.016) or ΔKtrans_D14 (HR 0.47, 95% CI 0.23-0.98, p = 0.038) were associated with a better OS. Among the clinical variables, ORR was associated with both PFS (p = 0.001) and OS (p = 0.005). DCR was associated with PFS (p = 0.002), but not OS (p = 0.089). Cox multivariable analysis revealed that ΔKtrans_D14 (p = 0.002) remained an independent predictor of PFS after controlling for ORR and DCR. An early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict favorable survival outcomes in participants with HCC receiving 2nd-line targeted therapy after sorafenib failure.

Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy.

PURPOSE: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 TRM; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 TRM and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 TRM, and CD39+ or PD-L1+ subsets of CD8 TRM were correlated with tumor response and overall survival (OS). RESULTS: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0-92.6%) of tumor-infiltrating CD8 T cells were TRM. In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 TRM cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 TRM-high, CD39+ CD8 TRM-high, and PD-L1+ CD8 TRM-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 TRM-high, CD39+ CD8 TRM-high, or PD-L1+ CD8 TRM-high, tumors, had significantly prolonged OS (p = 0.0429). CONCLUSIONS: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 TRM or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC.

Impact of expanded strong opioid availability on opioid prescription patterns in patients with cancer: A population-wide cohort study in Taiwan.

Background One of the major barriers to adequate cancer pain management in Taiwan is the limited prescription options regarding strong opioids. Internationally recommended strong opioids, including oxycodone and hydromorphone, were not introduced in Taiwan until late 2014. We analysed the patterns in opioid prescription for cancer pain management, after the introduction of new opioid options. Methods All inpatient and outpatient clinical visits from January 1, 2012, to December 31, 2017, with the diagnosis of cancer and the analgesic prescriptions were collected from the database of National Health Insurance, Taiwan, and analysed. Opioids were grouped into strong opioids, weak opioids, and guideline non-recommended opioids. Findings A total of 1, 292, 905 patients with cancers were included. Approximately 50% of patients used analgesics, 50% of which were opioids; the proportions were stable during the study period. The annual cumulative opioid use per patient (defined daily dose, DDD) significantly decreased from 36•41±102•59 (Mean±SD) in 2012 to 32•42±100•99 in 2017 (p < •001). The annual cumulative strong opioid use per patient increased significantly from 17•54±89•23 in 2012 to 19•28±94•97 in 2017 (+9•90%, p < •001). In parallel, the annual cumulative weak opioids use per patient decreased from 18•64±40•81 in 2012 to 13•04±26•79 in 2017 (-30•04%, p < •001). Among extended-release strong opioids, the use of transdermal fentanyl significantly decreased after oxycodone and hydromorphone were introduced (p < •001). Interpretation Increased therapeutic options in strong opioid prescriptions led opioid prescription patterns to evolve towards international cancer pain management guidelines. In addition, increased accessibility to a wider range of different strong opioids may facilitate more efficient opioid titration and rotation - and thus decrease, not increase, the opioid usage. Funding This study was supported by Ministry of Science and Technology, Taiwan (MOST-106-2314-B-002-213 and MOST-108-2314-B-002-072-MY3), Ministry of Health and Welfare, Taiwan (MOHW109-TDU-B-211-114002), National Taiwan University Hospital, Taipei, Taiwan (NTUH-103-002314 and NTUH. 105-S2954), and National Center of Excellence for Clinical Trial & Research, National Taiwan University Hospital, Taipei, Taiwan (NCTRC201208 and NCTRC201603).

An Exploratory Study for the Association of Gut Microbiome with Efficacy of Immune Checkpoint Inhibitor in Patients with Hepatocellular Carcinoma.

BACKGROUND: Gut microbiome has been associated with the efficacy of immune checkpoint inhibitors (ICI) in patients with various types of cancers but not yet in hepatocellular carcinoma (HCC). AIMS: To investigate the association between gut microbiome and efficacy of ICI in patients with HCC. METHODS: Patients with HCC who were scheduled to receive ICI were prospectively enrolled. Fecal samples were collected within 7 days before initiation of ICI (baseline) and 8 weeks later. Gut microbiome was assessed using 16S rRNA sequencing and shotgun whole-genome sequencing and correlated with objective response (complete or partial response), disease control (objective response or stable disease for ≥16 weeks), and overall survival. RESULTS: Thirty-six patients with HCC were enrolled, and 20 of them provided both baseline and 8-week feces. Alpha diversity, richness, and compositions of baseline gut microbiome indicated no difference between responders and nonresponders or between disease control and nondisease control groups. For the 20 paired feces, immunotherapy did not change any of the major microbiome features. No specific taxa were enriched in patients with objective response. Three taxa-Bifidobacterium, Coprococcus, and Acidaminococcus-were enriched in patients with disease control. However, the baseline abundance of these three taxa did not predict overall survival benefit. CONCLUSIONS: In this exploratory study, we failed to disclose any overt association of gut microbiome with the efficacy of ICI in patients with HCC. A larger prospective study is warranted for definite conclusion.

Eg5 as a Prognostic Biomarker and Potential Therapeutic Target for Hepatocellular Carcinoma.

BACKGROUND: The kinesin Eg5, a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in hepatocellular carcinoma (HCC). METHODS: HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model. RESULTS: A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS (p < 0.001) or DFS remained (p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control. CONCLUSION: High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.